TDP-43 is a major pathological protein in amyotrophic lateral sclerosis (ALS) and some forms of frontotemporal dementia (FTD) and is also present in ubiquitinated inclusions seen in other neurodegenerative diseases. How TDP-43 contributes to age-dependent neurodegeneration is largely unknown. TDP-43, an evolutionarily highly conserved RNA-binding protein mostly localized to the nucleus, participates in transcriptional repression, alternative splicing, mRNA trafficking, and possibly other aspects of RNA metabolism. However, its functions in postmitotic neurons have not been extensively studied. Normally, TDP-3 has a diffuse nuclear distribution. In diseased neurons, however, TDP-43 and its processed fragments aggregate into cytoplasmic ubiquitinated inclusions. Thus, loss of the normal function ofTDP-43 might contribute to neurodegeneration, perhaps in concert with other mechanisms, such as a toxic gain-of-function for TDP-43 fragments. In this R21 application, we propose to investigate the normal functions of endogenous TDP-43 in postmitotic neurons, which will likely provide important insight into the molecular mechanisms underlying TDP-43-related neurodegeneration. PUBLIC HEALTH RELEVANCE: In this application, we will test the hypothesis that loss of TDP-43 activity affects neuronal structural integrity therefore contributes to eventual neurodegeneration associated with a number of age-dependent neurodegenerative diseases. To this end, we will use fruitfly Drosophila as our primary model system for all the proposed studies.